Signalling Events Associated with Phase II Enzyme Induction The Role of Map Kinases

Chemotherapeutic drugs, natural products, and oxidative stress can modulate various extracellular signaling events and potentate stress-related gene transcription. The key components of these pathways linking extracellular events to intracellular responses are members of the mitogen-activated protein kinases (MAPK). MAPK are proline-directed serine/threonine kinases that mediate phosphorylation cascades involved in both cell survival and apopto-sis. c-Jun N-terminal kinase (JNK), extracellular-regulated kinase (ERK), and p38 kinase are three cascades recognized in the mammalian cells. Each can function in phosphorylating transcription factors such as c-jun, ATF2, c-Myc, and Nrf2 inducing gene expression of a wide range of targets, including genes containing an ARE in their promoter regions. The importance of MAP kinases in phase II detoxification enzyme induction is exemplified by the fact that inhibitory studies using chemical agents and/or generation of dominant negative mutants significantly reduced the expression of phase II detoxification enzymes. Yu et al. demonstrated an involvement of ERK in ITC-induced NQO1 activity. In hepa1c1c7 and HepG2 cells sulfo-raphane stimulates ERK2 activity leading to the induction of NQO1. Blocking of the signaling cascade using specific inhibitors or a mutated ERK2 transfected into cells attenuated NQO1 activity (145). The same group also reported that p38 kinase acts as a negative regulator of ARE gene expression. Inhibition of p38 activity increased the level of ARE reporter gene activity by several enzyme inducers including sulforaphane (146). Likewise, the inhibition of ERK and p38 MAP kinases prevents the binding of the Nrf2 transcription factor to gGCS genes (147).

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